This invention relates to ring fused pyrazole derivatives with CRF activity, and associated pharmaceutical compositions, and methods for use as therapeutic agents.
Corticotropin releasing factor (CRF) or hormone (CRH) is one of several neurohormones synthesized by specific hypothalamic nuclei in the brain where it activates the transcription of the pro-opiomelanocortin (POMC) gene resulting in release of adrenocorticotropic hormone (ACTH) and beta-endorphin from anterior pituitary cells (Vale et al, Science 213, 1394-1397 (1981)). The fundamental role of CRF is to prepare the organism for an appropriate response to various stressors such as physical trauma, insults of the immune system and social interactions. CRF also has CNS effects by acting at higher centers in the brain, particularly cortical regions where there is a widespread distribution of CRF neurons. CRF is believed to be a key intermediary in communication between the immune, central nervous, endocrine and cardiovascular systems (Sapolsky et al, Science 238, 522-524 (1987)). The role played by CRF in integrating the response of the immune system to physiological, psychological and immunological stressors has been described in the art, e.g. J. E. Blalock, Physiological Reviews 69, 1 (1989) and J. E. Morley, Life Sci. 41, 527 (1987).
CRF antagonists are effective in the treatment of a wide range of stress-related illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorder and cyclothymia; chronic fatigue syndrome; eating disorders such as obesity, anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; pain perception such as fibromyalgia; headache; stress-induced gastrointestinal dysfunction such as irritable bowel syndrome (IBS), colonic hypersensitivity or spastic colon; hemorrhagic stress; ulcers; stress-induced psychotic episodes; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; asthma; psoriasis; allergies; premature birth; hypertension; congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimer""s disease, senile dementia, Parkinson""s disease and Huntington""s disease; head or spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; psychosocial dwarfism; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; stress-induced immune dysfunctions; immune suppression and stress-induced infections; cardiovascular or heart related diseases; fertility problems; and/or human immunodeficiency virus infections. Accordingly clinical data suggests that CRF receptor antagonists may represent novel antidepressants and/or anxiolytic drugs that may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF.
In view of the above, efficacious and specific antagonists of CRF are desired as potentially valuable therapeutic agents for the treatment of psychiatric disorders and neurological diseases. It is thus desirable to discover new CRF antagonists.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
This invention relates to compounds comprising Formula I or Formula II: 
wherein:
R1 is xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94CRcRdRe, CO2Ra, or xe2x80x94C(O)NRaRb; or R1 is hydrogen, halogen, cycloalkenyl, aryl, or heteroaryl, where each aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, halogen, haloalkyl, cyano, nitro, xe2x80x94C(O)NRaxe2x80x2Rbxe2x80x2, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl;
R2 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, aryl, or arylalkyl, wherein said aryl or arylalkyl is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen;
R3 and R4 are each independently selected from hydrogen and C1-6alkyl, or R3 and R4 are taken together with the carbon to which they are attached to form a C3-6cycloalkyl ring;
Ar is aryl or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl;
Ra and Rb are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C1-6alkylthioalkyl, carboxyalkyl, C1-6alkoxycarbonyl, C1-6-alkoxy-C1-3alkylcarbonyl, acyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, di-C3-6cycloalkylC1-3alkyl, C1-6heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C5-8heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenylalkyl, phenylsulfonyl optionally substituted as described for phenyl below, and C1-3alkyl substituted with both a C3-6cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl; or
Ra and Rb are taken together with the nitrogen to which they are attached form an heterocyclyl or heteroaryl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole, and imidazole, where each of said rings is optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino, and phenyl, wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group;
Rc is hydrogen, hydroxy, C1-6alkoxy, or xe2x80x94NRaxe2x80x2xe2x80x3Rbxe2x80x2xe2x80x3;
Rd and Re are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C1-6alkylthioalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, di-C3-6cycloalkyl-C1-3alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C1-3alkyl, and C1-3alkyl substituted with both a C3-6cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen; or
Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C1-6heteroalkylidenyl, C3-6cycloalkylidenyl, C3-6cycloalkyl-alkylidenyl, C3-6cycloalkylalkyl-alkylidenyl, C3-6heterocyclylidenyl, C3-6heterocyclyl-C1-3alkylidenyl, C3-6heterocyclylalkyl-C1-3alkylidenyl, aryl-C1-3alkylidenyl, aryl-C1-3alkyl-alkylidenyl, heteroaryl-C1-3alkylidenyl, and heteroarylalkyl-C1-3alkylidenyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen; or
Rd and Re are taken together with the carbon to which they are attached to form a cycloalkyl or heterocyclyl ring;
Raxe2x80x2xe2x80x3 and Rbxe2x80x2xe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C1-6alkylthioalkyl, carboxyalkyl, C1-6alkoxycarbonyl, C1-6-alkoxy-C1-3alkylcarbonyl, acyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, di-C3-6cycloalkyl-C1-3alkyl, C1-6heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C5-8heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C1-3alkyl, and C1-3alkyl substituted with both a C3-6cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl; or
Raxe2x80x2xe2x80x3 and Rbxe2x80x2xe2x80x3 are taken together with the nitrogen to which they are attached form an heterocyclyl or heteroaryl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole, and imidazole, where each of said rings is optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino, and phenyl, wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group;
n is an integer selected from 0, 1 and 2;
a is a single or double bond;
providing that when n is 0, R1 is not hydrogen; when n is 0 and a is a double bond, R4 is absent; and when n is 1 or 2, a is a single bond;
or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In one embodiment, a compound of Formula I is described: 
wherein R1, R2, R3, R4, Ar, a, and n are as defined above.
In another embodiment, compounds of Formula III are described: 
wherein the integer n is 1 or 2, and R1, R2, R3, R4, and Ar are as defined above.
In another embodiment, compounds of Formula III are described, wherein Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, and R1, R2, R3, and R4 are as defined above.
In one aspect, such compounds are described wherein R3 and R4 are each independently selected from hydrogen and methyl.
In another aspect, such compounds are described wherein Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
In another aspect, such compounds are described wherein Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, halogen, haloalkyl, cyano, alkylamino, dialkylamino, and nitro.
In another aspect, such compounds are described wherein R2 is hydrogen, C1-6alkyl, or C1-6alkylcarbonyl.
In another embodiment, compounds of Formula IV are described: 
wherein Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, halogen, haloalkyl, cyano, alkylamino, dialkylamino, and nitro, R2 is hydrogen, C1-6alkyl, or C1-6alkylcarbonyl, R3 and R4 are each independently selected from hydrogen and methyl; and R1 is as defined above.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Rc is hydroxy; and Rd and Re are as defined above.
In one aspect, such compounds are described wherein Rd and Re are each independently selected from the group consisting of hydrogen, C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen.
In one alternative, such compounds are described wherein Rd and Re are each independently selected from the group consisting of C1-alkyl, C1-6alkoxyalkyl, aryl, and heteroaryl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen.
In another aspect, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another alternative, such compounds are described wherein Rd and Re are taken together to form a cycloalkyl or heterocyclyl group.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Re is selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen; and Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C1-6heteroalkylidenyl, C3-6cycloalkylidenyl, C3-6cycloalkyl-alkylidenyl, C3-6cycloalkylalkyl-alkylidenyl, C3-6heterocyclylidenyl, C3-6heterocyclyl-C1-3alkylidenyl, C3-6heterocyclylalkyl-C1-3alkylidenyl, aryl-C1-3alkylidenyl, aryl-C1-3alkyl-alkylidenyl, heteroaryl-C1-3alkylidenyl, and heteroarylalkyl-C1-3alkylidenyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen.
In one alternative, such compounds are described wherein Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C3-6cycloalkyl-alkylidenyl, aryl-C1-3alkylidenyl, and heteroaryl-C1-3alkylidenyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Re is selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, and heteroaryl, where the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen; and Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C3-6cycloalkyl-alkylidenyl, C3-6heterocyclyl-C1-3alkylidenyl, aryl-C1-3alkylidenyl, and heteroaryl-C1-3alkylidenyl, wherein each of said aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, amino, alkylamino, and dialkylamino.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Rc is hydrogen; and Rd and Re are as defined above.
In one aspect, such compounds are described wherein Rd and Re are each independently selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen.
In one alternative, such compounds are described wherein Rd and Re are each independently selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, aryl, and heteroaryl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen; R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-6alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94NRaRb; xe2x80x94C(O)NRaRb; or xe2x80x94CRcRdRe, where Rc is xe2x80x94NRaxe2x80x3Rbxe2x80x3; Rd and Re are each independently selected from the group consisting of hydrogen and C1-9alkyl; and Ra, Rb, Raxe2x80x2xe2x80x3, and Rbxe2x80x2xe2x80x3 are as defined above.
In one aspect, such compounds are described wherein Ra, Rb, Raxe2x80x3, and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C3-6cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In one alternative, such compounds are described wherein Ra and Rb, or Raxe2x80x2xe2x80x3 and Rbxe2x80x2xe2x80x3, are taken together with the nitrogen to which they are attached form an heterocyclyl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, and imidazoline, where each of said rings is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, and aminocarbonylamino, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94NRaRb; Ra is selected from the group consisting of hydrogen, C1-9alkyl, and C1-6alkoxyalkyl; and Rb is selected from the group consisting of C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In one aspect, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Rxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Rxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is CRcRdRe; Rc is NRaxe2x80x2xe2x80x3Rbxe2x80x2xe2x80x3; Rd and Re are each independently from the group consisting of hydrogen and C1-9alkyl; Raxe2x80x2xe2x80x3 is selected from the group consisting of hydrogen, C1-9alkyl, and C1-6alkoxyalkyl; and Rbxe2x80x2xe2x80x3 is selected from the group consisting of C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In one aspect, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94ORa, and Ra is as defined above.
In one aspect, such compounds are described wherein Ra is selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In another aspect, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted or 2,4,6-trisubstituted phenyl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted phenyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is aryl or heteroaryl, where said aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
In one alternative, such compounds are described wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
In another embodiment, compounds of Formula III are described, wherein Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, and R1, R2, R3, and R4 are as defined above.
In one aspect, such compounds are described wherein R3 and R4 are each independently selected from hydrogen and methyl.
In another aspect, such compounds are described wherein Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
In another aspect, such compounds are described wherein Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, alkylamino, and dialkylamino.
In another aspect, such compounds are described wherein R2 is hydrogen, C1-6alkyl, or C1-6alkylcarbonyl.
In another embodiment, compounds of Formula IV are described wherein Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, alkylamino, and dialkylamino, R2 is hydrogen, C1-6alkyl, or C1-6alkylcarbonyl, R3 and R4 are each independently selected from hydrogen and methyl; and R1 is as defined above.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9 alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Rc is hydroxy; and Rd and Re are as defined above.
In one aspect, such compounds are described wherein Rd and Re are each independently selected from the group consisting of hydrogen, C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen.
In one alternative, such compounds are described wherein Rd and Re are each independently selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, aryl, and heteroaryl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen.
In another aspect, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another alternative, such compounds are described wherein Rd and Re are taken together to form a cycloalkyl or heterocyclyl group.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Re is selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen; and Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C1-6heteroalkylidenyl, C3-6cycloalkylidenyl, C3-6cycloalkyl-alkylidenyl, C3-6cycloalkylalkyl-alkylidenyl, C3-6heterocyclylidenyl, C3-6heterocyclyl-C1-3alkylidenyl, C3-6heterocyclylalkyl-C1-3alkylidenyl, aryl-C1-3alkylidenyl, aryl-C1-3alkyl-alkylidenyl, heteroaryl-C1-3alkylidenyl, and heteroarylalkyl-C1-3alkylidenyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen.
In one alternative, such compounds are described wherein Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C3-6cycloalkyl-alkylidenyl, aryl-C1-3alkylidenyl, and heteroaryl-C1-3alkylidenyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Rxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Re is selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, and heteroaryl, where the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen; and Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C3-6cycloalkyl-alkylidenyl, C3-6heterocyclyl-C1-3alkylidenyl, aryl-C1-3alkylidenyl, and heteroaryl-C1-3alkylidenyl, wherein each of said aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, amino, alkylamino, and dialkylamino.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Rc is hydrogen; and Rd and Re are as defined above.
In one aspect, such compounds are described wherein Rd and Re are each independently selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen.
In one alternative, such compounds are described wherein Rd and Re are each independently selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, aryl, and heteroaryl, where each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen; R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94NRaRb; xe2x80x94C(O)NRaRb; or xe2x80x94CRcRdRe, where Rc is xe2x80x94NRaxe2x80x2xe2x80x3Rbxe2x80x2xe2x80x3; Rd and Re are each independently selected from the group consisting of hydrogen and C1-9alkyl; and Ra, Rb, Raxe2x80x2xe2x80x3, and Rbxe2x80x2xe2x80x3 are as defined above.
In one alternative, such compounds are described wherein Ra, Rb, Raxe2x80x2xe2x80x3, and Rbxe2x80x2xe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C3-6cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In another alternative, such compounds are described wherein Ra and Rb, or Raxe2x80x2xe2x80x3 and Rbxe2x80x2xe2x80x3, are taken together with the nitrogen to which they are attached form an heterocyclyl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, and imidazoline, where each of said rings is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, oxo, alkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, and aminocarbonylamino, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94NRaRb; Ra is selected from the group consisting of hydrogen, C1-9alkyl, and C1-6alkoxyalkyl; and Rb is selected from the group consisting of C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In one alternative, such compounds are described, wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94CRcRdRe; Rc is xe2x80x94NRaxe2x80x2xe2x80x3Rbxe2x80x2xe2x80x3; Rd and Re are each independently selected from the group consisting of hydrogen and C1-9alkyl; Raxe2x80x2xe2x80x3 is selected from the group consisting of hydrogen, C1-9alkyl, and C1-6alkoxyalkyl; and Rbxe2x80x2xe2x80x3 is selected from the group consisting of C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said aryl or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In one alternative, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is xe2x80x94ORa, and Ra is as defined above.
In one alternative, such compounds are described wherein Ra is selected from the group consisting of C1-9alkyl, C1-6alkoxyalkyl, C3-6cycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl.
In another alternative, such compounds are described wherein R2 is C1-6alkyl; R3 and R4 are hydrogen; and Ar is a 2,4-disubstituted, 2,6-disubstituted, or 2,4,6-trisubstituted pyridin-3-yl, and the substituents are independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen and C1-9alkyl.
In another embodiment, compounds of Formula III are described, wherein R3 and R4 are each independently selected from hydrogen and methyl, Ar is a di- or tri-substituted pyridinyl, and the substituents are each independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x3Rbxe2x80x3, where Raxe2x80x3 and Rbxe2x80x3 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, the integer n is 1 or 2, R2 is as defined above; and
R1 is aryl or heteroaryl, where said aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
In one alternative, such compounds are described wherein the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, halogen, haloalkyl, cyano, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
The invention further relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula I or Formula II, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier.
The invention further relates to a method of treating a subject that has a disease state that is alleviated by treatment with a CRF receptor antagonist, wherein said method comprises administering to said subject a therapeutically effective amount of the compound of Formula I or Formula II.
In one embodiment, a method of treating a subject that has a disease state comprising disorders of the CNS is described herein. In another embodiment, a method of treating a subject with a disease state comprising phobias, stress related illnesses, mood disorders, eating disorders, generalized anxiety disorders, stress induced gastrointestinal dysfunctions, neurodegenerative diseases, or neuropsychiatric disorders is described herein.
The invention further relates to a process for preparing a compound of Formula I, where a is a single bond, comprising:
(a) treating a compound of formula: 
where R3, R4, and Ar are as defined in claim 1, with a compound of formula: 
where R is alkyl, to form a first intermediate of formula: 
(b) treating the first intermediate with a compound of formula:
R2xe2x80x94NHNH2,
where R2 is as defined in claim 1, to form a second intermediate of formula: 
In one embodiment, the process further comprises (c) treating the second intermediate with a compound of formula:
Raxe2x80x94OH,
where Ra is as defined in claim 1, to form a compound of Formula I, wherein R1 is xe2x80x94ORa.
In one alternative, the process further comprises (c) treating the second intermediate with a brominating reagent to form a third intermediate of formula: 
In another embodiment, the process further comprises (d) converting the third intermediate into an anion of formula: 
(e) treating the anion with a compound of formula: 
where Rd and Re are as defined in claim 1, to form a compound of Formula I, wherein R1 is xe2x80x94CRcRdRe, and Rc is hydroxy.
In one alternative, the process further comprises (e) treating the anion with a compound of formula:
C(O)2,
to form a compound of Formula I, wherein R1 is xe2x80x94CO2Ra.
In another embodiment, the process further comprises (d) treating the third intermediate with a compound of formula: 
where Arxe2x80x2 is aryl or heteroaryl, where each aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl, to form a compound of Formula I, wherein R1 is aryl or heteroaryl, where each aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, halogen, haloalkyl, cyano, nitro, and xe2x80x94NRaxe2x80x2Rbxe2x80x2, where Raxe2x80x2 and Rbxe2x80x2 are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl.
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9caxe2x80x9d, xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise.
xe2x80x9cAlkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d means a monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a divalent linear or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylethylene, 3-methylpropylene, 2-ethylethylene, pentylene, hexylene, and the like.
xe2x80x9cAlkoxyxe2x80x9d means a radical xe2x80x94OR, wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d denotes one or more alkoxy group(s) as defined above which is (are) bonded to an alkyl group as defined above. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, t-butyloxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl, 1,4-dimethoxypropyl, including their isomers. C1-6alkoxyalkyl denotes a group wherein the alkyl portion is comprised of 1-6 carbon atoms exclusive of carbon atoms in the alkoxy portion of the group.
xe2x80x9cCycloalkylxe2x80x9d means a monovalent saturated carbocyclic radical consisting of one or more rings, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, and sulfonylamino, unless otherwise indicated. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cycloheptyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical xe2x80x94Rxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 is an alkylene radical, and Rxe2x80x3 is a cycloalkyl radical as defined herein. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means a monovalent unsaturated carbocyclic radical consisting of one or more rings, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, and sulfonylamino, unless otherwise indicated. Examples of cycloalkenyl radicals include, but are not limited to, cyclobuten-1-yl, 3-ethylcyclobuten-1-yl, cyclopenten-1-yl, 3-fluorocyclohepten-1-yl, and the like.
xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d means the radical fluoro, bromo, chloro, or iodo, and combinations thereof.
xe2x80x9cHaloalkylxe2x80x9d means a lower alkyl radical as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of haloalkyl radicals include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic radical of 6 to 12 ring carbon atoms having at least one aromatic ring, with the understanding that the attachment point of the aryl radical will be on an aromatic ring. The aryl radical is optionally substituted independently with one or more substituents, preferably one to three substituents, selected from alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, thio, methylenedioxy or ethylenedioxy. More specifically the term aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, 3,4-methylenedioxyphenyl, 1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroisoquinoline-7-yl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonyloxy, xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, thio, methylenedioxy or ethylenedioxy. More specifically the term heteroaryl refers to monocyclic aromatic moieties having 5 to 6 ring atoms, including 1 to 2 heteroatoms, and includes, but is not limited to, pyridinyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, and pyrimidinyl, and derivatives thereof. In addition, the term heteroaryl refers to bicyclic aromatic moieties having 9 to 10 ring atoms, including 1 to 3 heteroatoms, and includes, but is not limited to, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolinyl, 5,6,7,8-tetrahydroquinolinyl, isoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzimidazolyl, benzisoxazolyl, and benzothienyl, and derivatives thereof.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined herein wherein one, two, or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of xe2x80x94ORa, xe2x80x94NRbRc, and xe2x80x94S(O)nRd (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein Ra is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and Rb and Rc are independently selected from the group consisting of hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, Rd is hydrogen, alkyl, cycloalkyl, and cycloalkylalkyl. When n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated non-aromatic monocyclic or bicylic radical of 3 to 10 ring atoms in which one or two ring atoms are heteroatom containing groups selected from NRxe2x80x2, O, or S(O)n (where Rxe2x80x2 is alkyl, heteroalkyl, or hydrogen, and n is an integer from 0 to 2), the remaining ring atoms being carbon. The heterocyclyl radical is optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, and acyl. The term heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, tetrahydropyrimidin-5-yl, tetrahydropyrimidin-1-yl, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, pyrrolinyl, imidazolinyl, tetrahydroquinolin-1-yl and tetrahydroisoquinolin-2-yl, and the like.
xe2x80x9cArylalkylxe2x80x9d means a radical xe2x80x94Rxe2x80x2Rxe2x80x3 where Rxe2x80x2 is an alkylene radical and Rxe2x80x3 is an aryl radical as defined herein. Examples of arylalkyl radicals include, but are not limited to, 4-fluorophenylmethyl, 3,4-dichlorophenylethyl, and the like.
xe2x80x9cHeteroarylalkylxe2x80x9d means a radical xe2x80x94Rxe2x80x2Rxe2x80x3 where Rxe2x80x2 is an alkylene radical and Rxe2x80x3 is an heteroaryl radical as defined herein. Examples of heteroarylalkyl radicals include, but are not limited to, such as 3-pyridinylmethyl, 4-chloropyrimidin-2-ylmethyl, 2-thiophen-2-ylethyl, and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94Rxe2x80x2Rxe2x80x3 where Rxe2x80x2 is an alkylene radical and Rxe2x80x3 is an heterocyclyl radical as defined herein. Examples of heterocyclylalkyl radicals include, but are not limited to, tetrahydropyran-2-ylmethyl, 2-piperidinylmethyl, 3-piperidinylmethyl, morpholin-1-ylpropyl, and the like.
xe2x80x9cAlkylaminoxe2x80x9d means a radical xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 is hydrogen or alkyl, and Rxe2x80x3 is an alkyl radical as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, ethylamino, cyclopropylmethylamino, dicyclopropylmethylamino, dimethylamino, methylethylamino, diethylamino, di(1-methylethyl)amino, and the like.
xe2x80x9cAcylxe2x80x9d means a formyl radical of the formula xe2x80x94C(O)H, or a carbonyl radical of the formula xe2x80x94C(O)Rxe2x80x2, where Rxe2x80x2 is selected from the group consisting of C1-18alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl, heterocyclylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, or amino, as defined herein, where said amino is optionally monosubstituted or disubstituted with alkyl, or said amino is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group.
xe2x80x9cAlkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R and Rxe2x80x2 are independently an alkyl radical or hydrogen, as defined herein. Examples of alkylidenyl radicals include, but are not limited to, ethylidenyl, propylidenyl, butylidenyl, and the like.
xe2x80x9cCycloalkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R and Rxe2x80x2 are taken together with the carbon to which they are attached to form a bivalent cycloalkyl radical, as defined herein. Examples of cycloalkylidenyl radicals include, but are not limited to, cyclopentylidenyl, 3-fluorocyclohexylidenyl, and the like.
xe2x80x9cCycloalkyl-alkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is a cycloalkyl radical, as defined herein. Examples of cycloalkyl-alkylidenyl radicals include, but are not limited to, cyclopropylmethylidenyl, cyclohexylmethylidenyl, 1-cyclopentylethylidenyl, and the like.
xe2x80x9cCycloalkylalkyl-alkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is a cycloalkylalkyl radical, as defined herein. Examples of cycloalkylalkyl-alkylidenyl radicals include, but are not limited to, 2-cyclopentylethylidenyl, 1-cyclohexylpropyliden-2-yl, and the like.
xe2x80x9cHeteroalkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an heteroalkyl radical, an haloalkyl radical, an alkyl radical, or hydrogen, and Rxe2x80x2 is an heteroalkyl radical or an haloalkyl radical, as defined herein. Examples of heteroalkylidenyl radicals include, but are not limited to, 3,3,3-trifluoropropylidenyl, 2-hydroxybutylidenyl, 3-aminopropylidenyl, and the like.
xe2x80x9cHeterocyclylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R and Rxe2x80x2 are taken together with the carbon to which they are attached to form a bivalent heterocyclyl radical, as defined herein. Examples of heterocyclylidenyl radicals include, but are not limited to, pyrrolidinyliden-2-yl, tetrahydropyranyliden-4-yl, piperidinyliden-4-yl, and the like.
xe2x80x9cHeterocyclyl-alkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is an heterocyclyl radical, as defined herein. Examples of heterocyclyl-alkylidenyl radicals include, but are not limited to, 4-piperidinylmethylidenyl, 4-methyl-1-piperazinylmethylidene, and the like.
xe2x80x9cHeterocyclylalkyl-alkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is an heterocyclylalkyl radical, as defined herein. Examples of heterocyclylalkyl-alkylidenyl radicals include, but are not limited to, 2-(tetrahydropyran-4-yl)ethylidenyl, 1-(piperidin-3-yl)propyliden-2-yl, and the like.
xe2x80x9cArylalkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an aryl radical, an alkyl radical, or hydrogen, and Rxe2x80x2 is an aryl radical, as defined herein. Examples of arylalkylidenyl radicals include, but are not limited to, 4-chlorophenylmethylidenyl, 6,7-dimethoxynaphth-2-ylmethylidenyl, and the like.
xe2x80x9cArylalkyl-alkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is an arylalkyl radical, as defined herein. Examples of arylalkyl-alkylidenyl radicals include, but are not limited to, 2-(4-trifluoromethylphenyl)ethylidenyl, 1-(3,4-dichlorophenyl)propyliden-2-yl, and the like.
xe2x80x9cHeteroarylalkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is an heteroaryl radical, as defined herein. Examples of heteroarylalkylidenyl radicals include, but are not limited to, 3-pyridinylmethylidenyl, 4-chloro-2-pyrimidinylmethylidenyl, and the like.
xe2x80x9cHeteroarylalkyl-alkylidenylxe2x80x9d means a bivalent radical xe2x95x90CRRxe2x80x2, wherein R is an alkyl radical or hydrogen, and Rxe2x80x2 is an heteroarylalkyl radical, as defined herein. Examples of heteroarylalkyl-alkylidenyl radicals include, but are not limited to, 2-(4-trifluoromethylpyrimidinyl)ethylidenyl, 1-(thiophen-2-yl)propyliden-2-yl, and the like.
xe2x80x9cPhenylsulfonylxe2x80x9d means a monovalent radical C6H5SO2xe2x80x94. A phenyl group can be unsubstituted or substituted with one or more suitable substituents.
xe2x80x9cAlkoxycarbonylxe2x80x9d means a monovalent radical xe2x80x94C(O)xe2x80x94OR, wherein R is a lower alkyl radical as defined herein. Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, and the like.
xe2x80x9cAlkoxyalkylcarbonylxe2x80x9d means a monovalent radical xe2x80x94C(O)xe2x80x94Rxe2x80x94ORxe2x80x2, wherein R is an alkylene radical as defined herein and Rxe2x80x2 is a lower alkyl radical as defined herein. Examples of alkoxyalkylcarbonyl radicals include, but are not limited to, methoxymethylcarbonyl, ethoxymethylcarbonyl, and the like.
It is contemplated that the definitions described herein may be appended to form chemically-relevant combinations, such as xe2x80x9cheteroalkylaryl,xe2x80x9d xe2x80x9chaloalkylheteroaryl,xe2x80x9d xe2x80x9carylalkylheterocyclyl,xe2x80x9d xe2x80x9calkylcarbonyl,xe2x80x9d xe2x80x9calkoxyalkyl,xe2x80x9d and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that a subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptional bondxe2x80x9d means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
xe2x80x9cLeaving groupxe2x80x9d means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
xe2x80x9cProtective groupxe2x80x9d or xe2x80x9cprotecting groupxe2x80x9d means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive oxygen atoms present in the reactants. Acceptable protective groups for alcoholic or phenolic hydroxyl groups, which may be removed successively and selectively include hydroxyl groups protected as acetates, haloalkyl carbonates, benzyl ethers, alkylsilyl ethers, heterocyclyl ethers, methyl or alkyl ethers, and the like. Protective or blocking groups for carboxyl groups are similar to those described for hydroxyl groups, and are preferably tert-butyl, benzyl or methyl esters.
xe2x80x9cAmino-protecting groupxe2x80x9d means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It is preferred to use either BOC or CBZ as the amino-protecting group because of the relative ease of removal, for example by exposure to mild acids in the case of BOC, e.g., trifluoroacetic acid or hydrochloric acid in ethyl acetate as a solvent; or by catalytic hydrogenation in the case of CBZ.
xe2x80x9cHydroxy-protecting groupxe2x80x9d means the protecting group that preserves a hydroxy group that otherwise would be modified by certain chemical reactions. Suitable hydroxy-protecting groups include ether-forming groups that can be removed easily after completion of all other reaction steps, such as the benzyl or the trityl group optionally substituted in their phenyl ring. Other suitable hydroxy-protecting groups include alkyl ether groups, the tetrahydropyranyl, silyl, trialkylsilyl ether groups, and the allyl group.
xe2x80x9cDeprotectionxe2x80x9d or xe2x80x9cdeprotectingxe2x80x9d means the process by which a protective group is removed after the selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. Deprotecting reagents for protected hydroxyl or carboxyl groups include potassium or sodium carbonates, lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalysts, or boron tribromide, and the like.
xe2x80x9cInert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d means the solvent inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
xe2x80x9cIsomerismxe2x80x9d means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereoisomersxe2x80x9d, and stereoisomers that are non-superimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d.
xe2x80x9cChiral isomerxe2x80x9d means a compound with one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixture.xe2x80x9d When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al. Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
xe2x80x9cGeometric Isomersxe2x80x9d means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
xe2x80x9cAtropic isomersxe2x80x9d means the isomers owing their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond.
xe2x80x9cSubstantially purexe2x80x9d means at least about 90 mole percent, more preferably at least about 95 mole percent, and most preferably at least about 98 mole percent of the desired enantiomer or stereoisomer is present compared to other possible configurations.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
xe2x80x9cCrystal formsxe2x80x9d (or polymorphs) means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
xe2x80x9cSolvatesxe2x80x9d means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
xe2x80x9cProdrugxe2x80x9d or xe2x80x9cpro-drugxe2x80x9d means a pharmacologically inactive form of a compound which must be metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. Prodrugs of a compound of Formula I or Formula II are prepared by modifying one or more functional group(s) present in the compound of Formula I or Formula II in such a way that the modification(s) may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula I or Formula II wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of Formula I or Formula II is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group respectively. Examples of prodrugs include, but are not limited to, esters (e.g. acetate, dialkylaminoacetates, formates, phosphates, sulfates and benzoate derivatives) and carbamates of hydroxy functional groups (e.g. N,N-dimethylcarbonyl), esters of carboxyl functional groups (e.g. ethyl esters, morpholinoethanol esters), N-acyl derivatives (e.g. N-acetyl), N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals, and enol esters of ketones and aldehyde functional groups in compounds of Formula I or Formula II, and the like.
The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound. Reference to a compound herein includes prodrug forms of a compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: xe2x80x9cProdrugs and Drug delivery Systemsxe2x80x9d pp.352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs. Ed. by E. B. Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press, Oxford, 1980.
xe2x80x9cSubjectxe2x80x9d means mammals and non-mammals. Mammals means any member of the Mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term xe2x80x9csubjectxe2x80x9d does not denote a particular age or sex.
xe2x80x9cTherapeutically effective amountxe2x80x9d means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
xe2x80x9cDisease statexe2x80x9d means any disease, condition, symptom, or indication.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease state includes:
(1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state;
(2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or
(3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
xe2x80x9cMood disordersxe2x80x9d or xe2x80x9caffective disordersxe2x80x9d means psychopathologic conditions in which a pervasive disturbance of mood constitutes the core manifestation. These terms subsume anxiety and related neuroses, especially the depressive form. Examples of xe2x80x9cmood disordersxe2x80x9d or xe2x80x9caffective disordersxe2x80x9d include, but are not limited to, depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, unipolar disorder, bipolar disorder with manifestations of insomnia and eating disorder, dysthymic disorder, double depression, morbid and clinical depression, mania and cyclothymia.
In general, the nomenclature used in this Application is based on AUTONOM(trademark) v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.
For example, a compound of Formula I wherein R1 is 4-hydroxyheptan-4-yl, R2 is methyl, R3, and R4 are hydrogen, Ar is 2-chloro-4,6-dimethyl-phenyl, and n is 1 is named 4-[7-(2-chloro-4,6-dimethyl-phenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-heptan-4-ol.
The compounds of this invention are CRF antagonists, and as such are expected to be effective in the treatment of a wide range of stress-related illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorder and cyclothymia; chronic fatigue syndrome; eating disorders such as obesity, anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; pain perception such as fibromyalgia; headache; stress-induced gastrointestinal dysfunction such as irritable bowel syndrome (IBS), colonic hypersensitivity or spastic colon; hemorrhagic stress; ulcers; stress-induced psychotic episodes; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; asthma; psoriasis; allergies; premature birth; hypertension; congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimer""s disease, senile dementia, Parkinsons""s disease and Huntington""s disease; head or spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; psychosocial dwarfism; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; stress-induced immune dysfunctions; immune suppression and stress-induced infections; cardiovascular or heart related diseases; fertility problems; and/or human immunodeficiency virus infections.
These and other therapeutic uses are described, for example, in Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996, Chapter 26:601-616; and Coleman, R. A., Pharmacological Reviews, 1994,46:205-229.
The pharmacology of the compounds of this invention was determined by art recognized procedures. The CRF receptor binding affinity of test compounds can be determined by the intracellular CRF stimulated cAMP activity assay and the CRF Receptor Binding Assay as described in more detail in Example 3 and 4 respectively.
The compounds of Formulae I and II described herein may be prepared by standard synthetic methods. In particular, certain compounds of Formulae I and II may be prepared from intermediate bromopyrazole 7, the preparation of which is illustrated in Scheme 1 for Formula I, where R2, R3, R4, and n are as described above, and Ar, as described above, is for example phenyl optionally-substituted with one or more groups X. 
According to Scheme 1, optionally substituted aniline 1 s acylated with a carboxylic acid derivative, optionally substituted with groups R3 and R4, having an xcfx89-leaving group, such as halogen, to provide amide 2, which is subsequently cyclized under basic conditions onto the carbon possessing the leaving group to generate 3. Anilide lactam 3 is converted into the corresponding thione 4, deprotonated, C-acylated, and concurrently S-methylated to form methyl carboxylate 5. Treatment of 5 with R2-substituted hydrazine provides pyrazolinone-fused heterocycle 6, which is brominated to provide bromopyrazole 7. The pyrazole-fused heterocycles can also be similarly prepared with an aminoheteroaryl in place of the aniline. For example, compound 12d (Table 7) is prepared starting from 2-dimethylamino-4-methyl-5-amino pyridine (T. Ebara et al. JP54028330 [CAN 91:40904])
Intermediate bromopyrazole 7 is converted into the compounds of Formulae I and II, as illustrated in Scheme 2 for Formula I, where R2, R3, R4, Rd, Re, and n are as described above, and Ar, as described above, is for example phenyl optionally-substituted with one or more groups X. 
According to Scheme 2, intermediate bromopyrazole 7 is metallated and reacted with an Rd, R5-substituted aldehyde or ketone to provide alcohol 8a which may be eliminated to the corresponding alkene 9. It is appreciated that depending upon the reaction conditions, and the nature of Rd and R5, the double bond stereochemistry resulting from the elimination reaction to alkene 9 may be either an E-double bond, a Z-double bond, or a mixture of both in various ratios. Subsequent reduction of alkene 9, by hydrogenation for example, provides alkane 10. It is understood that Re as defined above corresponds to CH2xe2x80x94R5 or CHxe2x80x94R5 of alcohol 8a or alkene 9, respectively. Alternatively, bromopyrazole 7 is metallated and reacted with an Rd, Re-substituted aldehyde or ketone to provide alcohol 8b which may be deoxygenated, under radical conditions for example, to provide alkane 10.
Alternatively, intermediate bromopyrazole 7 is converted into the compounds of Formulae I and II, as illustrated in Scheme 3 for Formula I, where R2, R3, R4, Ra, Rb, and n are as described above, and Ar, as described above, is for example phenyl optionally-substituted with one or more groups X. 
According to Scheme 3, intermediate bromopyrazole 7 is metallated and reacted with carbon dioxide, or a carbon dioxide equivalent, to provide carboxylic acid 11. Acid 11 is converted to the corresponding amine 13 via an amide rearrangement, such as by the Curtius, Lossen, or Schmidt reaction, or as illustrated in Scheme 3 by the Hofmann reaction involving intermediate carbamate 12. Amine 13 is converted into the mono- or disubstituted amine 14 by reductive amination or successive reductive amination, respectively, using an appropriate aldehyde or ketone, and a reducing agent, such as sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Alternatively, amine 13 is converted into mono- or disubstituted amine 14 via acylation with an appropriate carboxlic acid derivative, such as the corresponding acid chloride, and reduction with an appropriate reducing agent such as diborane, borane-THF complex, and the like. Another alternative conversion of amine 13 to mono- or disubstituted amine 14 is via alkylation with an appropriate alkylating agent, such as methyl iodide, ethyl bromide, and the like, optionally under basic conditions. It is appreciated that each substituent Ra and Rb may be introduced using the same synthetic route described herein, or each substituent may be introduced by a different synthetic route described herein.
Alternatively, intermediate carboxylic acid 11 is converted into the compounds of Formulae I and II, as illustrated in Scheme 4 for Formula I, where R2, R3, R4, Ra, Rb, and n are as described above, and Ar, as described above, is for example phenyl optionally-substituted with one or more groups X. 
According to Scheme 4, intermediate acid 11 is converted into the corresponding amide 15 and may be further reduced to amine 16.
Alternatively, pyrazolinone-fused heterocyclic 6 is converted into the compounds of Formulae I and II, as illustrated in Scheme 5 for Formula I, where R2, R3, R4, Ra, and n are as described above, and Ar, as described above, is for example phenyl optionally-substituted with one or more groups X. 
According to Scheme 5, intermediate pyrazolinone-fused heterocycle 6 is converted into the corresponding alkoxypyrazole-fused heterocycle 17.
Alternatively, intermediate bromopyrazole 7 is converted into the compounds of Formulae I and II, as illustrated in Scheme 6 for Formula I, where R2, R3, R4, and n are as described above, and Ar, as described above, is for example phenyl optionally-substituted with one or more groups X. 
According to Scheme 6, intermediate bromopyrazole 7 is subjected to a metal-catalyzed aryl coupling reaction to provide an aryl pyrazole, as illustrated by, for example phenyl pyrazole 18, optionally substituted with one or more groups Y.
It is understood that the synthetic routes illustrated in Schemes 1-6 are suitable for preparing other compounds of Formulae I and II, including those compounds where Ar, as defined above, is for example naphthyl, pyrimidinyl, or pyridinyl, each of which may be optionally substituted. It is also appreciated that R2 as pertains to the illustrative synthetic sequences of Schemes 1-6 may be a protecting group, as defined above, which may be conveniently removed to provide R2 as hydrogen, or to introduce R2 as alkyl, aryl, acyl, or alkylsulfonyl, as defined above.
The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa bufter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to a skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Example 2.